Migraine is a common, debilitating disorder
that affects approximately 15% of the adult
population. There are two main types of
migraine: migraine without aura (MO), which
occurs in 85% of patients, and migraine with
aura (MA).
Altered monoaminergic neurotransmission is
involved in the pathogenesis of migraine.
5-Hydroxytryptamine has long been implicated in
migraine pathophysiology. Abnormalities in the
serotoninergic system have been observed before
and during migraine attacks and have been the
target of therapeutic developments. Clinical and
pharmacologic evidence supports the hypothesis
that dopamine (DA) is also involved in the
pathogenesis of migraine, and it could therefore
be considered the second putative protagonist in
headache. In particular, dopaminergic
hypersensitivity in migraineurs is suggested due
to the possibility of eliciting several symptoms
by dopaminergic agonists at doses that do not
affect nonmigraineurs
All studies on the familial occurrence of
migraine have found an increased frequency of
familial patients, suggesting the presence of a
genetic factor. Twin studies produced
conflicting results with respect to the
inheritability of migraine. A recent report
suggests that both MO and MA seem to be caused
by a combination of genetic and environmental
factors. Nevertheless, the mode of inheritance
has not been clarified and the causative genes
have not been identified. In 1993, a gene for
familial hemiplegic migraine, a rare autosomal
dominant subtype of MA, was mapped to chromosome
19pl3. Subsequently, a gene encoding an alpha 1
(ion-conducting) subunit of a voltage-gated
calcium channel was identified. The human gene
was designated CACNA1A.Various studies conducted
to test this locus for linkage with MO or MA
produced conflicting results.
Association studies using polymorphic
candidate genes are important strategies ln the
detection of genes that contribute only
partially toward an overall susceptibility to
developing complex diseases such as migraine.
One of the limitations of the latter design is
that population stratification can often produce
spurious results. Moreover, unless the gene has
a major effect, it may be difficult to replicate
independently even true genetic association
results. With regard to genes for dopamine
receptors (DR), five of which (DRD1, DRD2, DRD3,
DRD4, and DRD5) have been cloned and
characterized to date, only one study of
association with migraine has been published.
This recent study reported an association
between MA and a DA-related gene-DRD2-using the
classic case-control design.
As an alternative to case-control association
studies, a different design has been proposed
recently that is robust in the face of
geographic stratification because it is based on
families of affected individuals whose parental,
nontransmitted chromosomes serve as ethnically
matched controls. Nuclear families represent the
unit structure for such studies. Data can be
analyzed subsequently using methods such as the
Transmission Disequilibrium. Test (TDT). The
original use intended for the TDT was to test
for linkage with a marker located near a
candidate gene in subjects in whom disease
association had already been found. However,
even in the absence of previous evidence of
association, the TDT is a valid tool that can be
used to test any marker (or a set of markers)
for which data are available from parents and
affected offspring.
The assumption that the disorder within the
isolate is less heterogeneous genetically
compared with similar syndromes in outbred
groups contributed to the success of population
isolate mapping. In this regard Cavalli-Sforza
and Piazza reported that Sardinians are one of
the most genetically deviant populations in
Europe.
We applied the family-based association
methodTDT to a sample of 50 nuclear Sardinian
families with MO to test an association between
this type of migraine and some candidate genes
related to the dopaminergic system. Moreover, to
increase the probability of detecting an
association with DArelated genes, a subgroup of
probands with enhanced DA sensitivity based on
the presence of both nausea and yawning
during the migraine attack was analyzed.
The current article reports the findings of a
genetie study used to test the DA receptor genes
DRD2, DRD3, and DRD4 for an involvement in
migraine using, for the first time, an isolated
population and a family-based association method
(TDT).
[...]
Discussion. The current study, carried
out using the family-based method (TDT),
demonstrated a positive association between
allele 1 of DRD2 and the subgroup of
dopaminergic migraine. Considerable evidence
supports an involvement of the dopaminergic
system in the control of nausea and yawning
as well as their importance as core symptoms in
migraine. Therefore, our a priori hypothesis of
an association between DA-related genes and
dopaminergic migraine was warranted.
Several arguments suggest a possible
involvement of DA in migraine pathophysiology.
Apomorphine, a classic dopaminergic agonist, is
able to trigger true migraine attacks in
patients affected by PD disease and migraine.
Moreover, dopaminergic agonists induce
exaggerated dopaminergic-associated phenomena of
migraine such as yawning, nausea,
vomiting, hypotension, and syncope in
migraineurs at a dosage that is ineffective in
nonmigraineurs. Dopaminergic antagonists have
been proposed as antimigraine drugs. Apomorphine
bas a cerebral vasodilatory effect and increases
blood flow significantly in the middle cerebral
artery in migraineurs. This increase is not
present with placebo. The antidopaminergic
property of flunarizine, a widely used
prophylactic drug in migraine, suggests that the
dopaminergic system may play a role in its
clinical efficacy.
An increased density of dopamine D5 receptors
in peripheral blood lymphocytes of migraineurs
has been reported recently, further suggesting
the presence of an altered dopaminergic function
in migraine. All these observations support the
hypothesis that migraine is, at least in part,
characterized by dopaminergie
hypersensitivity.
Our data should be interpreted while bearing
several considerations in mind. Although allele
1 is the less common form. of DRD2, it is
unlikely that it represents the sole or major
factor in the development of MO. Nevertheless we
cannot ignore the fact that in a subgroup of MO,
the gene of the D2 receptor plays a pathogenetic
role in the illness. The intronic noncoding
position of the polymorphisin studied might be
linked closely to a funetional mutation,
modifying the expression of the DRD2 gene.
Alternatively, the same might be in linkage
disequilibrium with another closely linked
locus. Allelic frequencies may vary between
populations of different origin. In our study
the allelic frequencies observed in the control
group are similar to those reported previously
for a white population. Thus we may conclude
that the functional significance of this DRD2
allelic association might be related to DA
hypersensitivity in migraine.
To our knowledge, this is the first study of
candidate genes related to the dopaminergic
system-such as DRD2, DRD3, and DRD4-in migraine
using a family-based association approach. Very
recently the first case-control association
study performed in white population suggested a
positive association between MA and the DRD2
NeoI alleles. In particular, Peroutka et al.
suggested that the presence of the DRD2 NcoI C
allele has a significant effect on
susceptibility to MA compared with a control
group as well as with individuals with MO. The
apparent discrepancies with our data may be
explained by the fact that we used a different
statistical approach and a population with a
high genetic homogeneity. Moreover, our finding
of a positive association between MO and the
DRD2 gene was obtained in a subgroup of
migraineurs enriched with dopaminergic
symptoms.
Our data, in agreement with the cited report,
suggest that a genetic approach could be useful
in providing molecular support to the hypothesis
that hypersensitivity of the dopaminergic system
may represent the pathophysiologic basis of
migraine, at least in a subgroup of patients.
Moreover, these data may be relevant to the
usefulness of very low doses of D2 agonists as
prophylactic agents in migraine.
Because of the small size of the sample
examined, the recruitment of additional triads
and the replication of data in other populations
is necessary to clarify further the role of DRD2
in migraine.
